Abstract P2-16-01: The Kinesin-like protein Kif11 is essential for the Survival of TP53-mutant Triple Negative Breast Cancer Cells
Authors: Amanda Lanier, Abhijit Mazumdar, William Tahaney, Powel Brown
Journal: Cancer Research (2023)

Abstract Background: Breast cancer is the most commonly diagnosed non-cutaneous malignancy in American women and one of the leading causes of cancer deaths. Breast cancer can be divided into several subtypes, the most aggressive of which is Triple-Negative Breast Cancer (TNBC), a disease with few targeted therapies. TP53 mutations are found in 80% or more of TNBCs. However, direct targeting of mutant TP53 has been difficult. To identify drugs that can specifically induce the death of TP53-mutant breast cancers, we conducted a drug screen in TP53-mutant and TP53-wild type breast cancer cells. Through this combined in silico and in vitro drug screen, we discovered that TP53 mutant TNBC cells have an increased sensitivity to KIF11 inhibition as compared to TP53 wild-type cells. Hypothesis: We hypothesize that TP53 mutational status confers sensitivity of triple-negative breast cancer cells to KIF11 inhibition. Methods: We obtained data on TP53 mutational status, KIF11 mRNA expression levels, and clinical characteristics from publicly-available TCGA, METABRIC, and CCLE datasets. To demonstrate the effect of KIF11 inhibition on cell growth, we treated TP53 mutant and wild-type breast cancer cell lines with the small molecule KIF11 inhibitor SB-743921 and KIF11 siRNAs. Cell counts were obtained through staining with DAPI or Hoechst nuclear stains and imaging on the MetaXPress PICO instrument. To determine protein expression of p53 and Kif11 across various cell lines, western blotting was performed. We then investigated the biological mechanisms of growth inhibition by DRAQ7 staining and flow cytometry analysis following Annexin V-PI staining. Results: Using cell growth assays we demonstrated that TP53 mutant cells are more sensitive to KIF11 inhibition. We next utilized cell lines in which TP53 mutations had been introduced into TP53 wild-type cells to show that overexpression of a TP53 mutant gene can sensitize cells to KIF11 inhibition. Using assays of proliferation and apoptosis, we showed that TP53 mutant breast cancer cells treated with a KIF11 inhibitor undergo cell death. Using publicly-available datasets of breast cancers, we showed that KIF11 is upregulated in TNBCs and TP53 mutant cancers, and that high expression of KIF11 in breast cancer is correlated with poorer clinical prognosis. Conclusions: Our results show that the Kif11 protein is essential for the survival of TP53 mutant TNBC cells. Inhibitors of Kif11 induce death of TP53 mutant TNBCs and thus, this kinesin-like protein involved in cell spindle mechanics is a potential target for the treatment of these aggressive cancers. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Numbers TL1TR003169 and UL1TR003167. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also supported by the John Charles Cain Endowment. Citation Format: Amanda Lanier, Abhijit Mazumdar, William Tahaney, Powel Brown. The Kinesin-like protein Kif11 is essential for the Survival of TP53-mutant Triple Negative Breast Cancer Cells [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-16-01.